Mechanistic Studies on the Palladium-Catalyzed Direct Arylation of Imidazoles

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NIVERSITÀ DEGLI

S

TUDI DI

P

ISA

Facoltà di Scienze Matematiche, Fisiche e Naturali

Corso di Laurea Magistrale in

CHIMICA

Indirizzo Chimico Organico

C

LASSE

LM-54 (Scienze chimiche)

Mechanistic Studies on the Palladium-Catalyzed

Direct Arylation of Imidazoles

Relatore Candidato

Prof. Fabio Bellina Luca Alessandro Perego

Controrelatore

Dr. Fabio Marchetti

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Abstract

Some mechanistic aspects of the palladium-catalyzed direct arylation of imidazole derivatives at the C5 position with aryl halides have been investigated. Differently from previous studies on similar transformations, the focus was not only on the C-H activation step, but on the whole catalytic cycle.

Deuterium kinetic isotope effect (KIE) experiments have been carried out to demonstrate that C-H bond cleavage is involved in the turnover-limiting step of the catalytic cycle. Reactivity experiments on 1-aryl-2-methyl-1H-imidazoles showed that the reaction under study is faster for electron-deficient imidazole substrates.

PPh3-ligated organopalladium species have been shown to be unlikely intermediates of

the catalytic cycle when PPh3 is used as an auxiliary ligand. The interactions between

1,2-dimethyl-1H-imidazole (dmim) and PPh3-ligated organopalladium complexes have

been studied in detail. PPh3, used in conjunction with Pd(OAc)2 as a catalyst precursor

(2:1 molar ratio), is oxidized to PPh3O under the reaction conditions. The reaction thus

proceeds through imidazole-ligated organopalladium intermediates. The kinetics of the oxidative addition of aryl halides to dmim-ligated Pd(0) species has been characterized in a Pd(dba)2/dmim model system.

Complexes of formula ArPd(dmim)3I have been isolated and characterized for the first

time. They behave as a mixture of trans-[ArPd(dmim)2I] and free, uncoordinated dmim

in apolar solvent, while in polar media they partially dissociate to give [ArPd(dmim)3]+.

The latter cationic species has been shown to be active towards the direct arylation of dmim at room temperature in the presence of AcO-_{as a base. Preliminary kinetic data}

point out that C-H bond cleavage occurs by a concertated metalation-deprotonation (CMD) mechanism with AcO-_{acting as an outer-sphere base.}

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Riassunto

Sono stati esaminati alcuni aspetti meccanicistici della reazione di arilazione diretta catalizzata da palladio di derivati imidazolici alla posizione C5 con alogenuri arilici. Diversamente dagli studi precedenti su trasformazioni simili, non è stato analizzato solo il passaggio dell’attivazione del legame C-H, ma è stato considerato il ciclo catalitico nel suo insieme.

Sono stati effettuati esperimenti di effetto isotopico cinetico al deuterio per dimostrare che la rottura del legame C-H avviene nello stadio più lento del ciclo catalitico. È stato mostrato che specie organopalladio che hanno PPh3 come legante non sono intermedi

plausibili del ciclo catalitico. Studi di reattività su 1-aril-2-metil-1H-imidazoli indicano che la reazione in esame è più veloce per substrati imidazolici elettron-deficienti.

Le interazioni fra l'1,2-dimetil-1H-imidazolo (dmim) e specie organopalladio con leganti PPh3 sono state studiate in dettaglio. Quando PPh3 è usata insieme a Pd(OAc)2 come

precursore catalitico (in rapporto molare 2:1), essa è ossidata a PPh3O nelle condizioni

di reazione. Il coupling procede, dunque, attraverso specie di organo-palladio in cui il substrato imidazolico stesso funge da legante. La cinetica dell’addizione ossidativa di alcuni alogenuri aromatici a specie di Pd(0) con dmim come legante è stata caratterizzata in un sistema modello Pd(dba)2/dmim.

Alcuni complessi di formula ArPd(dmim)3I sono stati isolati e caratterizzati per la prima

volta. Essi si comportano come una miscela di trans-[ArPd(dmim)2I] e dmim non legato

in solventi apolari, mentre in mezzi polari essi si dissociano parzialmente a dare anche [ArPd(dmim)3]+. Queste specie cationiche sono attive nei confronti della reazione di

arilazione diretta di dmim a temperatura ambiente, in presenza di AcO-_{come base. Uno}

studio preliminare della cinetica di tale reazione suggerisce che la rottura del legame C-H avviene attraverso un meccanismo di metallazione-deprotonazione concertata (CMD) in cui AcO-_{agisce come base non coordinata (sfera esterna).}

È stato proposto un ciclo catalitico modificato sulla base dei nuovi dati sperimentali raccolti.

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1 Introduction

In the last two decades the field of the transition metal-catalyzed direct (hetero)arylation reactions of (hetero)arene C-H bonds with (hetero)aryl halides and pseudohalides has earned significant attention. Among the variety of aryl-heteroarenes, arylazoles are important structural units, frequently found in natural products,1–5

pharmaceuticals6,7_{and organic functional materials}8–12_{. Due to their widespread}

applications, the development of straightforward functional group-tolerant synthetic methods for their preparation is of considerable interest.

Many cross-coupling strategies have been developed so far for the formation of (hetero)aryl-(hetero)aryl bonds, with high yields, excellent selectivities and high functional group tolerance under mild conditions. The most common approach was the use of the traditional cross-coupling reactions promoted by transition metal catalysts (Scheme 1, a).13,14_{However, these methods suffer from lack of atom- and step-economy,}

as they involve the preactivation of both the coupling partners that afterwards lead to the formation metal-containing waste material.

An alternative to this approach is the Pd-catalyzed decarboxylative cross-coupling reaction between haloarenes and (hetero)aryl carboxylic acids (Scheme 1, b).15– 20_{In this case, the regioselectivity of the reaction is ensured by the carboxylic function}

and only carbon dioxide (apart from HX) is produced as waste.

In principle, the oxidative coupling of heteroarenes21,22_{, involving the activation of}

two (hetero)aryl C-H bonds (Scheme 1, c), represents the simplest and most convenient approach, especially when these transformations can be performed with molecular oxygen as the terminal oxidant. However, achieving regioselectivity in intermolecular oxidative arylation reactions still represents a challenge.

Scheme 1

A compromise between the aforementioned approaches, which is economical and waste-minimizing, involves the use of a (hetero)arene and a (hetero)aryl halide (Scheme

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1, d). The development and applications of transition metal-catalyzed direct arylation reactions of heteroarenes with aryl halides or pseudohalides have attracted a great attention. In fact, these reactions do not involve the use of stoichiometric amounts of organometallic reagents and result in a smaller number of reaction steps to obtain the required cross-coupling products with a concurrent reduction of waste.

The developments and advances in this area of research have been documented in excellent reviews published in 2007 by Fagnou,23_Lautens,24_{Satoh and Miura,}25

Gevorgyan26_{and Fairlamb,}27_{in 2009 by Ackermann,}28_{and Bellina and Rossi,}29_{in 2010}

by Catellani and Chiusoli30_{and Daugulis,}31_{in 2012 by Sun,}32_{and in 2014 by Doucet,}33

Hussain,34_{and Bellina and Rossi.}35,36_{A review published in 2013 by Glorius in which the}

use of C-H bond activation for the rapid construction and late-stage diversification of functional molecules was highlighted37_{is also worth mentioning.}

Broadly speaking, a direct arylation reaction is performed by heating a solution of the (hetero)arene substrate with an aryl halide or pseudohalide in the presence of a suitable palladium(II) or palladum(0) precatalyst and a base, generally chosen among inorganic weak bases (e.g. K2CO3, Cs2CO3, KOAc and Ag2CO3) (Scheme 2). A ligand,

most commonly a phosphine, may be present in the precatalyst or it may be added separately. Sometimes a supporting ligand is not added to the reaction mixture (“ligandless” conditions). A wide variety of additives (e.g. carboxylic acids, Ag(I) salts, quaternary ammonium salts and Cu(I) salts) have been shown to be beneficial in specific cases.

Scheme 2

The outcome of this kind of reactions is often highly dependent on the experimental conditions. For example, all the three position of the five-membered ring of the indole nucleus can be arylated with high selectivity by the judicious choice of precatalyst, base, solvent and additives. A Pd2(dba)3/DavePhos/NaOtBu system gives

arylation at N1 in high yields (Scheme 3),38_{with Pd(OAc)}

2/Ag2O/4-NO2-C6H4-COOH

arylation at C2 prevails (Scheme 4)39_{and an almost quantitative yield of the}

C3-arylated product is obtained with Pd(OAc)2/K2CO3/BnEt3NCl (Scheme 5)40.

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Scheme 4

Scheme 5

As another example, N-methyl-1H-imidazole is regioselectively arylated at C5 with a Pd(OAc)2/P(2-furyl)3/K2CO3 system (Scheme 6),41 N-methylimidazole and

imidazole are arylated selectively at C2 with a Pd(OAc)2 in the presence of a

supra-stoichiometric amount of CuI but without any added base (Scheme 7),42_{while the use of}

CuI alone with Cs2CO3 as a base leads cleanly to N-arylation of unsubstituted imidazole

(Scheme 8)43_.

Scheme 6

Scheme 7

Scheme 8

An in-depth mechanistic understanding of this kind of reactions may give insight useful for the development of new and more efficient catalytic systems in terms of activity under mild conditions, selectivity and functional group tolerance. The present is a mechanistic study of the palladium-catalyzed direct arylation reaction of imidazole derivatives at the C5 position. The next section is intended to give the reader a concise introduction to the most commonly employed experimental conditions used to effect this transformation.

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1.1 Direct arylation reactions of imidazole derivatives at C5 –

overview of literature results

In 1984 Ames found that the Pd-catalyzed intramolecular arylation of N-(2- bromophenyl)benzamide in 1-methyl-1H-imidazole at 190 °C did not give the required phenanthridone but, surprisingly, gave a 2-arylated-1-methyl-1H-imidazole (Scheme 9).44

Scheme 9

In 1992 Ohta and coworkers45_{reported that 1-methyl-1H-imidazole undergoes}

Pd(PPh3)4-catalyzed reaction with 2-chloro-3,6-dialkylpyrazines in refluxing DMA in the

presence of KOAc as a base to give 1-methyl-5-(2-pyrazinyl)-1H-imidazoles (Scheme 10). Yields were lowered by the concomitant formation of the 2,5-diarylated product.

Scheme 10

In 1998 Miura and coworkers46_{published a pioneering study on the direct}

arylations of imidazoles and other azoles. For that concerns imidazoles, they first optimized the reaction conditions for the direct C5 arylation of 1,2-dimethyl-1H-imidazole. The procedure described by them was not significantly different from the one previously reported by Otha and involving the more reactive chloropyrazines (Scheme 11). N N + Ar-X Pd(OAc)25 mol% PPh310 mol%

2 equiv base 2.0 equiv_DMF N

N Ar

Scheme 11

The choice of the base had a great influence on the yields of the reactions. With aryl bromides the best base was found to be K2CO3, while with aryl iodides Cs2CO3

performed better. The authors explained this result on the basis of the solubilities of the inorganic coproduct MX.46_{KBr is the least soluble of the inorganic bromides in DMF,}

while CsI is the least soluble among the alkali metal iodides. The ineffectiveness of Na2CO3 as the base has been explained with its poor solubility in organic solvents.

Amines also proved to be useless, perhaps because of their strong affinity for the palladium catalyst. Formation of the 2,5-diarylated product is an important side reaction under these conditions (Scheme 12).46

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Scheme 12

In 2005 Bellina and coworkers47_{conducted extensive studies towards the}

Pd-catalyzed selective C5 arylation of 1-arylimidazoles and found that this result could be achieved while suppressing C2 arylation and C2/C5 bisarylation when 1-arylimidazoles were reacted with electron poor, electron sufficient and moderately electron rich aryl bromides and iodides in DMF at 140 °C in the presence of CsF as the base and Pd(OAc)2/AsPh3 as the catalytic system (Scheme 13).

Scheme 13

In 2006 Sames and coworkers48_{reported that 1-SEM-1H-imidazole undergoes C5}

arylation with iodobenzene in DMA at 125 °C in the presence of CsOAc as the base and a bulky NHC-palladium complex as the catalyst (Scheme 14). The observed C5 selectivity was good, since the product was obtained along with 3-5% of C2 and C2/C5 arylation products.

Scheme 14

In 2009 Fagnou and coworkers49_{synthesized two 5-aryl-1-methyl-1H-imidazoles}

in moderate yields by the arylation of 1-methyl-1H-imidazole with aryl bromides using a Pd(OAc)2/PCy3HBF4 catalytic system, K2CO3 as the base and pivalic acid as an

additive (Scheme 15). Yields, however, are lower than that previously reported by Bellina and coworkers50_{and Fagnou’s conditions failed to give appreciable amounts of}

coupling products when applied to the arylation of 1-benzyl-2-methyl-1H-imidazole with 4-bromotoluene.

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Scheme 15

In 2009 Roger and Doucet51_{reported a protocol for the regioselective 5-arylation}

of 1-methyl-1H-imidazole using low palladium loadings (0.01-0.5 mol%) in the absence of a phosphine ligand with KOAc as the base (Scheme 16). 2-Substituted and 4-substituted aryl bromides proved to be suitable substrates, provided that they were not too electron-rich. A strong influence of the choice of the base was also observed.51

Scheme 16

In 2011 Murai and coworkers52_{investigated the applicability of [Pd(phen)}

2](PF6)2

as a catalyst for the selective C5 arylation of 1-methyl-1H-imidazole, but found that 2,5-diarylation was an important side reaction with this catalytic system and thus acceptable results have been obtained only with a large excess of 10 molar equiv of the imidazole substrate (Scheme 17).

Scheme 17

In 2011 Kumar and coworkers53_{reported that a bulky N-heterocyclic}

carbene-palladium complex efficiently catalyzes the C5 arylation of 1-methyl-1H-imidazole in moderate yields. Again a strong influence of the base has been observed. In addition to aryl bromides, aryl chlorides were found to be suitable substrates and gave yields only slightly lower than that obtained with aryl bromides. Selectivity over C2/C5 bisarylation was acceptable. Results with aryl chlorides are summarized in Scheme 18.

In the same year Kappe and coworkers50_{published conditions for the direct}

arylation of 1-methyl-1H-imidazole with a low catalyst loading (1 mol%) with the use of MW heating. Aryl bromides were reacted with the appropriate heteroarene in the presence of Pd(OAc)2 and the bulky, electron rich PCy3 using K2CO3 as the base and

pivalic acid (30 mol%) in DMF. Results concerning 2-unsubstituted imidazoles are summarized in Scheme 19.

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Scheme 18

Scheme 19

Between 2005 and 2009 Bellina and coworkers developed a generally applicable and selective method for the direct arylation of several N-substituted imidazoles at the C-5 position with aryl iodides and bromides. These conditions were suitable for N-methyl-, N-benzyl, N-aryl-imidazoles and involved the use of 5 mol% Pd(OAc)2, 10

mol% P(2-furyl)3, CsF as the base for aryl iodides and K2CO3 for aryl bromides, in

DMF or DMA as the solvent at 110 °C for methyl-imidazole and at 140°C for N-benzyl- and N-aryl imidazole (Scheme 20).41,47,54–56

Scheme 20

In 2013 Bellina and coworkers described a mild, general, added-ligand free palladium-catalyzed direct arylation of the 5-position of azoles (N-methylpyrazole, oxazole, thiazole, 1-methylimidazole) with aryl bromides, promoted by Pd(OAc)2 and

tetrabutylammonium acetate.57_{The reaction proceeded at a remarkably mild}

temperature (70 °C in DMA) for all the azoles studied, but for 1-methyl-1H-imidazole 110 °C are required (Scheme 21).57

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For convenience, the aforementioned procedures are summarized in Table 1 as applied to the common benchmark substrate 1-methylimidazole, together with some selected results.

Table 1 - Pd-catalyzed C5 arylation of N-methyl-1H-imidazole – comparison of literature protocols

Procedure Substrates Catalytic system Base Solvent,

temp. Selected examples

Miura 199846 PhBr (2 eq.) Pd(OAc)2 (10 mol%) PPh3 (20 mol%) K2CO3 (2 eq.) DMF, 140 °C G = H 53% C2/C5 bisarylation 33% PhI (2 eq.) Cs2CO3 (2 eq.) G = H 54% C2/C5 bisarylation 33% Bellina 200850 ArBr (1.5 eq.) Pd(OAc)2 (5 mol%) P(2-furyl)3 (10 mol%) K2CO3 (2 eq.) DMF, 110 °C G = Ph 80% G = OMe 49% Ar = 2-naphthyl 67% Fagnou 200949 ArBr, imidazole (2 eq.) Pd(OAc)2 (2 mol%) PCy3HBF4 (4 mol%) PivO (30 mol%) K2CO3 (1.5 eq.) DMA, 110 °C G = OMe 34% Ar = 2-naphthyl 40% Doucet 200951 ArBr, imidazole (2 eq.)

Pd(OAc)2 (5 mol%) KOAc (2 eq.) DMA, 150 °C G = OMe 42% G = Me 40% Murai 201152 ArBr, imidazole (10 eq.) [Pd(phen)2](PF6)2 (5 mol% ) Cs2CO3 (1 eq.) DMA, 150 °C G = CF3 74% Kumar 201153 ArBr, imidazole (1.5 eq.) (5 mol%) KOAc (2 eq.) DMA, 140 °C G = H 51% G = OMe 46% ArCl, imidazole (1.5 eq.) G = H 46% G = OMe 40% Kappe 201150 ArBr, imidazole (1.1 eq.) Pd(OAc)2 (1 mol%) PCy3 (2 mol%) pivalic acid (30 mol%) K2CO3 (1.5 eq.) DMF, 180 °C, sealed vessel, MW G = OMe 68% Bellina 201357 ArBr

(1.5 eq.) Pd(OAc)2 (5mol%)

Bu4NOAc (2.0 eq.) DMA, 110 °C G = H 75% G = OMe 82% G = 2-Me 68% selectivity > 0.91

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2 Mechanistic studies on the Pd-catalyzed direct

arylation of (hetero)arenes with aryl halides

Despite the great amount of literature devoted mainly to methodology development and synthetic applications of the Pd-catalyzed direct arylation of arenes and heteroarenes with aryl halides and pseudohalides, mechanistic works are comparatively few. Besides the general reviews that cover both synthetic an mechanistic aspects,23–37,58,59_{the state of}

the art of mechanistic studies on direct arylation reactions has been summarized by Echavarren in 201060_{and, for what concerns the CMD (Concerted}

Metalation-Deprotonation) mechanism, by Fagnou in the same year61_{and by Gorelsky in 2013}62_.

For simplicity, we will present the main results reported in the literature concerning the mechanistic understandig of the direct arylation reaction of arenes and heteroarenes subdivided by the kind of process which was proposed for C-H bond cleavage. The latter aspect, indeed, has been the main focus of most works. We will not discuss examples for which mechanistic hypotheses have been merely proposed without any significant experimental evidence in support of the claim.

2.1 Cleavage of the C-H bond in a S

E

Ar type process

At the time of earlier studies, the direct arylation of electron-rich five-membered heteroaromatics was commonly thought to take place by an electrophilic aromatic substitution mechanism, as first hypothesized by Miura.46_{A simplified overview is given}

in Scheme 22 (palladium ligands not shown for clarity) for a generic 1,3-azole.

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If the pre-catalyst is a palladium(II) compound, reduction to palladium(0) is effected by some species in the reaction environment. In the first step the aryl halide undergoes oxidative addition by a nucleophilic palladium(0) species. The palladium(II) organometallic compound thus obtained is electrophilic and can add to the arene with the formation of the classic Wheland intermediate. Azoles, indeed, are often classified as π-excessive systems, since the effect of the “pyrrole” type heteroatom predominates over that of the “pyridine” type nitrogen. In fact, many azoles are capable of entering into electrophilic substitutions reactions under very mild conditions and electrophilic palladation of arenes featuring metal directing groups by Pd(II) complexes has been known for long63_{. The reaction rate is expected to increase with electron-releasing}

substituents on the 1,3-azole, which stabilize the Wheland intermediate. The C5 position is generally the most favoured site for SEAr reaction for the 1,3-azoles,

according to both elementary resonance theory and quantum-mechanical computations and C5 selectivity is commonly found for direct arylation reactions in the absence of additives.64,65_{Coordination of electrophiles at the N3 site lowers somehow the reactivity}

towards SEAr, but does not change the C5 preference.65 An added base assists the

rearomatization of the Wheland intermediate by taking up a proton. C-C bond forming reductive elimination, which is known to proceed only when the organic residues are cis to each other66_{, finally yields the coupling product and regenerates palladium(0).}

Although a SEAr pathway is sometimes claimed, there are very few mechanistic

studies that show data supporting a SEAr mechanism for direct arylation reactions.

However, the formation of palladacycles by cyclization of suitably aryl substituted organopalladium derivatives is generally thought to happen through a SEAr mechanism.

In 1992 Catellani and Chiusoli67_{showed that the rates of the intramolecular ring closure}

of norbornyl-palladium derivatives 1 to form palladacylces 2 under the influence of KOPh as a base follows the reactivity pattern expected for SEAr with para-substituted

aryl groups (OMe>H>NO2, Scheme 23).

Scheme 23

Echavarren and coworkers found the same order of reactivity for the cyclization of three differently substituted (aryloxymethyl)palladium complexes 3 (Scheme 24).68

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19 Y O Pd Ph3P PPh₃ Cl PhOK CD₃CN, r.t. Y _O Pd Ph₃P PPh3 Y=OMe, H, NO₂ 3 4 Scheme 24

Moreover, in accordance to a classical SEAr pathway, no kinetic isotope effect

(KIE) was apparent (Scheme 25).68_{The formed palladacycles 4 are stable complexes and}

do not undergo reductive elimination to give strained 2H-benzoxetanes.

Scheme 25

An added equivalent of PPh3 inhibited the cyclization of 3 and the same

complexes with PPh3 replaced by bidentante phosphines cyclized in longer reaction

times. Ligand substitution, thus, is expected to play a role in this reaction and mechanism could be more complicated than it is apparent at first sight. Interestingly, the (2,2-dimethyl-2-phenylethyl)palladium complex 5, which readily cyclizes upon action of NaHMDS, after treatment with TfOH gives the isolable complex 6 featuring a π,η1

interaction with the ipso carbon of the phenyl ring, which may be of mechanistic significance (Scheme 26).69 Pd PMe₃ PMe₃ OTf NaHMDS Pd Me₃P PMe3 TfOH - [Me₃PH]OTf Pd TfO Me₃P 5 6 Scheme 26

In 2004 Gevorgyan and coworkers70_{reported a direct arylation of indolizines at}

C5 catalyzed by PdCl2(PPh3)2 in the presence of KOAc as the base. They found that

there is no measurable deuterium kinetic isotope effect (Scheme 27). Moreover, they established by competition experiments that the reactivity of 6-substituted indolizines towards direct arylation parallels the reactivity towards Friedel-Crafts acylation (Scheme 28).

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Scheme 27

Scheme 28

Attempts to trap a hypothetical Heck-type intermediate by insertion of a tethered olefinic moiety or by reduction with hydride donors invariably failed, thus making unlikely the existence of a carbopalladated intermediate (Scheme 29). These observations, together, were judged to be consistent with a SEAr pathway.70

Scheme 29

Interestingly, Snieckus and coworkers71_{obtained very similar results for the}

C5-arylation of a series of differently substitued 8-aryl-imidazo(1,5-a)pyrazines (7) catalyzed by Pd(OAc)2 and tBu2PMe·HBF4 in the presence of Cs2CO3: the reaction rate varied in

the order expected for an electrophilic aromatic substitution (4-OMe > 4-F > 3-NO2 >

4-NO2) and KIE was approximately 1 (Scheme 30). Nevertheless, based on the lack of

secondary negative KIE, SEAr was ruled out.

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In 2005 Sames and coworkers,72_{in a partially retracted work, described a}

regioselective arylation of N-substituted and N-unsubstituted indoles at the C2 position, instead of the usual C3 position for electrophilic substitutions. They observed a small KIE at the C2 position (kH/kD=1.2), but a significant KIE for the C3 position

(kH/kD=1.6, Scheme 31).

Scheme 31

Moreover, a Hammett plot was made for the C2 arylation of a series of 6-substituted indoles and a negative value was found for Hammett’s ρ (Scheme 32), thus suggesting a buildup of positive charge on the aromatic ring in the transition state. These data have been interpreted by the authors as indicative of a mechanism in which a C3-palladated intermediate first forms by electrophilic aromatic substitution, then isomerizes to the C2-metalated derivative and gives reductive elimination towards the observed coupling product (Scheme 33).72

Scheme 32 ArPdIIXL_n+ N R N R LnArPd _H SEAr Wheland intermediate isomerization N R PdArLn H base N R PdArLn reductive elimination N R Ar Scheme 33

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In 2007 Gevorgyan and coworkers73_{reported an arylation of triazole derivatives}

(8) at C5 catalyzed by Pd(PPh3)2Cl2 in the presence of nBu4NOAc as a base under

relatively mild conditions (100 °C). Again, no measurable KIE was found (Scheme 34) and the more electron rich MeO-substituted derivative 8a had greater reactivity, in accordance with a possible SEAr mechanism (Scheme 35).73

Scheme 34

Scheme 35

No KIE was also observed for the direct arylation at C5 of N-protected 2-amino-4-thiazolecarboxylates 9 by the use of an intermolecular competition experiment (Scheme 36).74

Scheme 36

In 2006 Mori and coworkers reported that [ArPd(2,2’-bipyridyl)X] (X=I, Br, Cl) (10) reacts with 2,3-dibromothiophene (11) in the presence of KF and AgNO3 as

activators to give the arylation product 12 in 64-78% yields at room temperature (Scheme 37).75,76_{An electrophilic aromatic substitution mechanism was postulated for}

this transformation.75 Pd N Ar X N + S Br AgNO34.0 equiv Br S Br Br Ar 2.4 equiv KF 4.0 equiv DMSO, r.t., 5 h (52-67%) Ar = 3,5-Me₂C₆H₃, 3,5-(CF₃)₂C₆H₃, 4-(COOEt)C₆H₄ X = I, Br, Cl 10 ₁₁ 12 Scheme 37

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The diaryl-metal intermediate have been isolated for the analogous platinum(II) complexes 13 (Scheme 38). These complexes are of interest for the mechanistic understanding of a quite general protocol for the arylation of thiophenes, thiazole, benzofurans and N-protected indole (Scheme 39).77

Scheme 38

Scheme 39

2.2 Cleavage of the C-H bond in a Concerted

Metalation-Deprotonation (CMD) process

In 2006 Fagnou and coworkers78_{developed a palladium−pivalic acid cocatalyst system}

that exhibits high reactivity in direct arylation of arenes, as illustrated by the high-yielding arylation of completely unactivated benzene with 4-bromotoluene (14) (Scheme 40). Pivalic acid, which is converted in the reaction environment to its potassium salt, is essential for the reaction to proceed.

Scheme 40

Competition studies showed that benzene reacts preferentially over the more electron rich-anisole and electron-deficient fluorobenzene reacts faster than benzene itself.78_{The reaction with anisole indicates that there is no electronic}

ortho,para-directing effect by the methoxy substituent but only a minor steric bias resulting in a small statistical preference for reaction at the meta and para positions (o,m,p ratio:

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22:53:25, Scheme 41). When fluorobenzene is used as a substrate, the o,m,p ratio in the arylation products is 22:3:1, indicating that C-H acidity is the leading contribution to the regioselectivity of the reaction (Scheme 41).

Scheme 41

The aforementioned experimental observations together with DFT analysis support the concerted metalation-deprotonation (CMD) pathway for this arylation reaction (Scheme 42). According to this mechanistic hypothesis, the pivalate anion acts as a “proton shuttle” and assists the simultaneous metalation and deprotonation of the arene while still coordinated to palladium, thus there is no proper Wheland intermediate. In the transition state there is no great buildup of charge on the aromatic ring, since electron-releasing substituents and electron-withdrawing substituents affect only moderately the rate of reaction. Pivalate bases were said to be more suitable than acetates since they are more soluble in organic solvents.78

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Prior and almost contemporaneously to the landmark work by Fagnou and coworkers on the direct arylation of unactivated benzene,78_{several reports of}

intramolecular direct arylations appeared in which chemo- and regioselectivity were not in agreement with an electrophilic mechanism. In 2004 Echavarren showed that the cyclization of N-(2-bromobenzyl)carbazole derivative 15 occurs with only slight preference for the more elctron-rich unsubstituted ring and that arylation can easily occur para to a nitro group (Scheme 43).

Scheme 43

In 2006 Fagnou and coworkers79_{showed that the cyclization of}

(2-bromobenzyloxy)arenes 16 occurs with the expected high para selectivity with respect to alkyl, methoxy, trifluoromethyl, nitro and carboxymethyl groups, but the para bias is significantly reduced for a chloro substitutent and the cyclization of the fluoro derivative occurs preferentially at the ortho postition (Scheme 44). The observation of a primary KIE by an intramolecular competition experiment (Scheme 45) led the authors to the conclusion that C-H cleavage occurs in the rate-determining step of the catalytic cycle,79

but it is well known that this conclusion cannot be drawn from this kind of experiment.80 Scheme 44 O Br _Pd(OAc) 23 mol% PCy₃HBF₄6 mol% K₂CO₃2.0 equiv DMA 130 °C O O D D kH/ kD= 4.25 Scheme 45

Echavarren and coworkers designed a set of elegant cyclizations of 1,1,2-triarylethanes 17 leading to 9-arylphenanthrenes 18 after aromatization with DDQ (Scheme 46, Scheme 47). Thus, while substrate 17a bearing a single fluorine substituent

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26

at C-4 (meta to the arylation site) has a modest preference towards arylation of the substituted ring, the selectively dramatically increases with substrates having fluorine substituents at the ortho positions (17b) and selectivity is almost complete for a trifluorophenyl moiety (17c) (Scheme 46).81,82_{The arylation of substrates with a}t_Bu

substituent (17d-e) showed that the latter group decreases the susceptibility of the ring to undergo arylation, in stark contrast to what expected for an electrophilic substitution (Scheme 47). Isotope effects were also determined by intramolecular competition between phenyl and pentadeuterophenyl groups (kH/kD=6.7 at 100 °C).82

Br (F)_n 1) Pd(OAc)2, L, K2CO3, DMA, 135 °C 2) DDQ, toluene (72-82%) (F)_n (F)_n L = Me2N PPh2 _3,5-(F)4-F (17a): 1.6 : 1.0 2(17b): 19 : 1.0 3,4,5-(F)₃(17c): 25 : 1.0 17 18 Scheme 46 Br 1) Pd(OAc)₂, L, K₂CO₃, DMA, 135 °C 2) DDQ, toluene (68%) Br 1) Pd(OAc)2, L, K2CO3, DMA, 135 °C 2) DDQ, toluene (81%) t_Bu t_Bu t_Bu t_Bu _F t_Bu _F t_Bu _F 1.0 : 1.5 1.0 : 2.3 17d 17e Scheme 47

The same effect of fluorine substitution was observed also for the intermolecular arylation of polyfluorinated arenes with aryl halides promoted by a Pd(OAc)2/tBu2MeP

catalyst system (Scheme 48): in every case fluorine substituents enhanced the reactivity, more so in the ortho position.83,84

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27 F F F F F F F F F F F F F F F F F F F F F F > > > > > > (F)_n Pd(OAc)₂5 mol% t_Bu 2MeP·HBF410 mol% K₂CO₃1.1 equiv DMA, 120 °C + ArX X = Cl, Br, I (F)_n Ar Reactivity order: Scheme 48

The intramolecular arylation on 5H-indeno[1,2-b]pyridine derivative 19 proceeded with selectivity at the pyridine ring to give 20 as the main product (Scheme 49).81,82

Scheme 49

The mechanism proposed for this transformation was a concerted metalation-deprotonation (CMD) in which carbonate or bicarbonate assisted the removal of the proton by acting either in an intramolecular or in a intermolecular fashion (Scheme 50).

Scheme 50

Interestingly, in contrast with the abovementioned reports, Kalyani and coworkers observed a bias for the cyclization with activation of the C-H bond of the more electron-rich phenyl ring in the case of the intramolecular reaction of mesylate and tosylate esters of a N,N-diaryl-2-aminophenol 21 leading to N-arylcarbazoles with a Pd(OAc)2/dcype catalyst system (Scheme 51).85,86 The authors did not give any

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Scheme 51

Phosphine-ligated arylpalladium carboxylates are typically proposed to react with heteroarenes or arens to form the diaryl-palladium complexes through the CMD pathway.61,62,78_{DFT calculations on this mechanism have been carried out and these}

studies suggested that those arypalladium carboxylates are competent to undergo C-H cleavage with various (hetero)arenes.61,87,88_{Hartwig and Tan prepared and characterized}

the complex [(2-Me-C6H4)Pd(PtBu3)(OPiv)] (22).89 Inconsistently with previous

proposals, they showed that these isolated organopalladium species do not react readily with benzene to form the arylation product in more than trace amounts (Scheme 52). The main organometallic product formed under those conditions was shown to be the cyclometalated dimer 23, formed by C-H activation of the t_Bu

3P ligand (Figure 1).

However, if the reaction with benzene was conducted in the presence of additives that consumed or displaced the phosphine ligand (O2, nHept4NBr, nHept4NOPiv) the product

appeared. trace 32% Pd O PtBu3 O K2CO32.5 equiv DMA, 110 °C 27% 22 Scheme 52 Figure 1

The catalytic reaction of 2-bromotoluene with benzene with a Pd(OAc)2/tBu3P/PivOH catalyst system and K2CO3 as the base, indeed gave

2-methylbiphenyl in 71% yield, together with 9.5% of the homocoupling product (Scheme 53).89

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29

Scheme 53

The anionic, “ligandless” species [(2-Me-C6H4)PdBr2]22- (24), already studied in

the context of the Heck reaction,90_{reacts with benzene under stoichiometric conditions}

in the presence of K2CO3 and PivOH to give a 57% yield of 2-methylbiphenyl (Scheme

54), thus showing the capability of “ligandless” species to effect the direct arylation of unfunctionalized arens. Moreover, the reaction of 4-bromotoluene with benzene catalyzed by Pd(OAc)2 alone was faster than in the presence of tBu3P and had

comparable selectivity. Under the conditions originally described by Fagnou78_(Scheme

40) with added DavePhos, a 76% yield of 4-methylbiphenyl was obtained and the reaction reached full conversion in 10 h. Without any added ligand, an 80% yield was obtained in only 4 h (Scheme 55).89

Scheme 54

Scheme 55

The addition of DavePhos did not make any significant difference in the KIE measured by intermolecular competition (Scheme 56) and in the product distribution of the competitive arylation of benzene and fluorobenzene (Scheme 57), in accordance with the hypothesis that the same phosphine-free species are active under both the sets of conditions.89

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30

Scheme 57

In summary, phosphine-ligated species were shown not to be competent species in the direct arylation of benzene. This conclusion was also supported by DFT calculations of the activation barriers with phosphine-ligated and solvent-ligated aryl-palladium pivalates.89_{The authors proposed that this behaviour may be linked to the}

steric properties of t_Bu

3P. tBu3P-ligated complexes usually contain only three ligands,

but higher-coordinated species or even anionic complexes seem to have better activity towards the direct arylation of arenes than tricoordinated species.89

Gorelsky and coworkers87,88_{performed a computational distortion-interaction}

analysis of the C−H bond cleavage of a wide range of (hetero)aromatics through the concerted metalation−deprotonation pathway in an attempt to quantify the contributions to the CMD reactivity. On the basis of this analysis, (hetero)arene substrates can be divided into three classes. For Class I arenes, the regioselectivity of C−H bond functionalization is controlled by the difference in the arene distortion energies. Class II includes the (hetero)arenes for which interaction energies with the metal catalyst are the determining factor in reactivity. Class III arenes are the (hetero)arenes in which both the distortion and interaction energies influence the C−H bond functionalization. In the opinion of the authors, this classification of the (hetero)arenes allows for an easier understanding of their reactivity.87,88_{The classification}

is summarized in Figure 2.

The analysis of the computed CMD reaction pathway also revealed that for some electron-rich and simple heteroarenes π-complexes are formed prior to the C−H bond cleavage step. In such intermediates, the arene fragments undergo only small distortion, refuting the idea of the formation of a Wheland intermediate that would possess strong Pd-(hetero)arene interaction.88_{The possibility of the existence of a}

continuum for the mechanism of C-H cleavage by transition metal carboxylate complexes was also evaluated. At one end of this continuum would lie the pure, stepwise electrophilic aromatic substitution pathway in which the M-C bond is fully formed before cleavage of the C-H bond occurs. On the other end would reside a fully concerted process in which the M-C bond is formed at the same time as the C-H bond is cleaved. For example, an Electrophilic Metalation Deprotonation (EMD) pathway was proposed by Sames and coworkers for the C-H cleavage for N-SEM-imidazoles, which is substantially a CMD mechanism in which concertation is only partial and a positive charge builds up on the heteroaromatic substrate in the transition state.91_This

hypothesis was disproved by the DFT studies performed by Gorelsky, which showed a high degree of concertation for all the arenes studied.88

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31 F F F F F H F F H F H Cl Cl H N O H OMe H S H S H F O H H _NN

Class I - regioselectivity is controlled by the arene distortion energy

O N S H H N S _H O N N _H N H N N N H

Class II - regioselectivity is controlled by the interaction energy

H N N O H N _O H N S H O S _H N H

Class III - regioselectivity is controlled by both interaction energy and distortion energy

Figure 2 – Classification of (hetero)arenes according to the factors that control regioselectivity in the CMD

pathway, as reported by Gorelsky and coworkers.88_{In bold the C-H bond that is preferentially cleaved.}

Ess and coworkers further analyzed the regioselectivity of C-H bond functionalization via the CMD pathway and found a kinetic/thermodynamic relationship that explains the observed regioselectivity for a wide variety of (hetero)arenes.92_{Coherently with a late character of the transitions state for C-H bond}

cleavage in [PhPd(PMe3)(OAc)] with acetate acting as a ligated base, metal-aryl bond

stability in the transition state is the main factor that correlates with the observed regioselectivity. For cases in which a neigbour pyridine-like nitrogen forms a stabilizing interaction through hydrogen bond with the coordinated AcOH, the contribution of hydrogen bonding must be excluded in order to correctly predict regioselectivity.92

A satisfactory linear correlation was found between computed activation barriers and aryl-metal bond energies in the transition state. This relationship suggests that

usually the strongest C-H bond will be preferentially activated since it will lead to the most stable Pd-C bond. However, there is no linear correlation between computed C-H bond dissociation energies and activation barrier values, since it is the developing metal

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aryl bond and not the breaking of the C-H bond that determines relative barrier heights.92

Gorelsky and coworkers also evaluated experimentally the influence of remote substituents on the reactivity of thiophenes towards direct arylation. A series of 2-substituted thiophenes was selected and relative reactivity assessed by competition experiments (Scheme 58). The order found (Scheme 58) is not that expected for an electrophilic substitution and it was in fair accordance with activation energies estimated by DFT calculations for a CMD pathway.88

S S H H G G' 0.50 equiv 0.50 equiv ArBr 0.10 equiv C, PivOH 30 mol% K₂CO₃, DMA, 100 °C R S Ar Ar G G' C = N Pd H H PCy3 Cl Reactivity: S _N S _CN S _COOi_{Pr S} _Cl S O S > > > > > Scheme 58

In 2010 Fagnou and coworkers reported a detailed mechanistic study on the arylation of pyridine N-oxides with aryl bromides with a Pd(OAc)2/tBu3P·HBF4/K2CO3

catalytic system (Scheme 59).93_{The dependence of the reaction rate on the}

concentrations of the various reactants has been examined. The reaction is first order with respect to the pyridine N-oxide (PyO) substrate, zeroth order with respect to the aryl bromide and t_Bu

3P and has order ½ with respect to the palladium precatalyst. A

KIE of 3.3 was measured by the independent determination of the rate constants for the reaction of pentadeuterio-PyO and the natural abundance analogue. These observations suggest that the oxidative addition is not turnover-determining, but the turnover limiting step involves the cleavage of the C-H bond. The half-order in the palladium concentration was said to be indicative of a dimeric resting state of the catalyst. The independence of the reaction rate from the presence of excess t_Bu

3P is also worth-noting,

indicating that the ligand is most likely present in the C-H bond functionalization transition state.93

Scheme 59

A reactivity study was also performed on a series of differently 4-substituted pyridine N-oxides (Scheme 60).93_{A Hammett plot was made by reporting the logarithms}

of the relative reaction rates against σm and a positive slope of 1.5 was obtained, which

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inconsistent with an electrophilic aromatic substitution pathway. An apparent Arrhenius activation energy of 18.5 kcal/mol was found for the reaction in Scheme 60 (G=NO2).93

Scheme 60

Surprisingly, when the reactivity of [PhPd(Pt_Bu

3)Br] (25) towards

4-nitropyridine N-oxide (26) was assessed under stoichiometric conditions in the presence of K2CO3 or KOPiv as bases, quite disappointing results were obtained: with K2CO3 (10

equiv) only 5% yield was reached, but yield increased to 29% with KOPiv (10 equiv) instead of K2CO3. The improvement obtained by using both the bases together was

negligible (Table 2).93_{The complex [PhPd(P}t_Bu

3)(OAc)] (27) was also studied. It gave

a comparatively low 48% yield of the expected arylation product with the highly reactive 4-nitropyridine N-oxide (Scheme 61). Again, added K2CO3 did not substantially

improve the yield.93_{These observations led the authors to underline the critical role of}

acetate, added with Pd(OAc)2 as a catalytic precursor, for the success of the reaction.

The authors may have overlooked the extremely scant solubility of K2CO3 in toluene as

a possible reason for the ineffectiveness of this base under stoichiometric conditions.

Table 2 – Effect of added bases (K2CO3 or KOPiv) on the direct arylation of 4-nitropyridine N-oxide with [PhPd(t_Bu₃_{P)Br) under stoichiometric condtions.}

Entry K2CO3 KOPiv NMR yield

1 - - 0

2 10 equiv - 5%

3 - 10 equiv 29%

4 10 equiv 10 equiv 31%

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In summary, the authors concluded that the species [ArPd(Pt_Bu

3)(OAc)] reacts

directly with pyridine N-oxides to give the arylation product and K2CO3 has the role of

regenerating AcO-_{from the co-product AcOH.}93_{This conclusion was challenged in 2012}

by Hartwig and coworkers, who examined the reaction of isolated [ArPd(Pt_Bu

3)(OAc)]

(28) with PyO (Ar = 3-(CH2F)-C6H4, the fluorinated group was introduced in order to

use 19_{F NMR spectroscopy for reaction monitoring).}94_{In contrast to a 77% yield}

obtained under catalytic conditions, the reaction of the isolated complex 28 with PyO at 120 °C in toluene formed the arylated PyO in a lower 52% yields (Scheme 62), consistently with the analogous experiments performed by Fagnou93_{. They found an}

induction period for the formation of the product, during which a cyclometalated complex [Pd(µ2_-OAc)(κ2

-t_Bu

2PCMe2-CH2)]2 (29) formed. The cyclometalated species was

obtained in 92% yield by heating the parent complex alone in toluene at 60 °C (Scheme 63).94

Scheme 62

Scheme 63

Much evidence pointed out that C-H functionalization of PyO actually occurs with the cyclometalated complex. Addition of said complex (1.0 equiv) to a solution of [ArPd(Pt_Bu

3)(OAc)] (28) and PyO gave the expected coupling product in 84% yield

without any induction period. The concentration of the cyclometalated complex 29 was constant during the reaction and no dependence of the reaction rate on the concentration of [ArPd(Pt_Bu

3)(OAc)] (28) was found, the reaction was zeroth order

also with respect to added [Pd(Pt_Bu

3)2]. The reaction, indeed, was firs order in PyO and

half order in the cyclometalated species 29, thus suggesting that the dimeric form is a resting state in a pre-equilibrium regimen with the catalitically active monomer 30 (Scheme 64).94_{The incongruence found by Fagnou and coworkers of a monomeric resting}

state and half-order dependence of the reaction rate on the concentration of palladium was thus explained.93

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35

At least two modes of cleavage of the C-H bond are conceivable: one in which the cyclometalated phosphine ligand is involved (mode A) and one in which acetate acts as a base (mode B) (Scheme 65). The observation that the analogous cyclometalated complex [PdBr(t_Bu

2PCMe2-CH2)]2, lacking an acetate ligand, did not catalyze the

reaction of [ArPd(Pt_Bu

3)(OAc)] (28) with PyO and that no deuterium incorporation

took place in the reaction of of the cyclometalated acetate 29 with PyO-d5, together

with DFT calculations, pointed out that acetate acts as a base.94

Scheme 65

The same role of the cyclometalated species 29 was also found for the direct arylation of benzothiophene. In this case it was possible to prepare independently the complexes bearing the heteroaryl residue by transmetalation of the corresponding organolithium compound (Scheme 66). The latter polar organometallic reagent is stable, differently from the notoriously fragile 2-pyridil organolithium derivatives. The PEt3

-stabilized 2-benzothienyl palladium species 31 was isolable, while the coordinatively unsaturated analogue (without PEt3) 32 was characterized only in situ. The

heteroaryl-palladium complexes reacted smoothly with [ArPd(Pt_Bu

3)(OAc)] (28) to give the

expected coupling product (Scheme 66).94

Scheme 66

On the basis of the previously described experimental results, a revised mechanism was proposed, featuring two different palladium centres with different roles (Scheme 67). The catalytic network comprises two merging catalytic cycle. The left cycle (Scheme 67) begins with oxidative addition of the aryl bromide to [(Pt_Bu

3)Pd(0)]

to form an arylpalladium(II) intermediate D. Exchange of acetate for bromide generates the arylpalladium acetate intermediate [ArPd(Pt_Bu

3)(OAc)] (28), which was formerly

thought93_{to cleave the heteroaryl C-H bond. Instead, new data imply that an}

arylpalladium(II) species undergoes transmetalation with a heteroaryl-cyclometalated intermediate B to form a heteroaryl aryl palladium species. Reductive elimination forms the new C-C bond of the 2-arylpyridine oxide product and regenerates Pd(0). The other cycle, shown at the right of Scheme 67, monomeric [Pd(OAc)(t_Bu

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fast pre-equilibrium with the inactive dimer [Pd(µ-OAc)(t_Bu

2PCMe2-CH2)]2 (29), reacts

with PyO to cleave the C-H bond and form the complex B containing the cyclometalated phosphine. This is the turnover-limiting step of the catalytic network.94

Results on the arylation of benzothiophene suggest that those results may pertain also to direct arylation of substrates different from PyO.

Scheme 67

The higher activity of the cyclometalated species than [ArPd(t_Bu

3P)(OAc)] (28),

also confirmed by activation barriers obtained by DFT calculations, was explained by the authors by proposing that the constrained ring makes the metal centre less hindered, facilitating the reaction with PyO.94

Gorelsky evaluated by DFT calculations the cleavage of C-H bonds for different arenes and heteroarenes via a CMD mechanism for both the non-cooperative process involving [ArPd(R3P)(OAc)] complexes and the cooperative process involving

cyclometalated [Pd(OAc)(t_Bu

2PCMe2-CH2)] (30). Calculated activation barriers in the

two processes indicate that the non-cooperative and cooperative process lead to the same regioselectivity for the arylation.95_{This demonstrates that regioselectivity is to be}

considered very carefully as a useful evidence in support of a mechanistic pathway (i.e. multiple related or unrelated mechanistic pathways could explain the same observed regioselectivity).

As we have seen so far in this account, isolated aryl-palladium complexes which are able to undergo C-H cleavage of (hetero)aromatic substrates without the need of additional activators and promoters have been scarcely documented. In 2012 Ozawa and coworkers96_{reported that [ArPd(µ-O}

2CR)(PPh3)]n complexes (Ar = Ph, 2-Me-C6H4,

2,6-Me2-C6H3; R = Me, tBu) successfully react with a great excess of 2-methylthiophene in

the absence of any additive to give 5-aryl-2-methylthiophenes in high yields (an example in Scheme 68). The reaction was accelerated in polar solvents (DMA > THF > 1,4-dioxane > toluene) and the presence of air increased the proportion of PhPh formed.

i_Pr

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37

Scheme 68

Reactivity increased with the bulkiness of the Ar group (Ph < 2-Me-C6H4 >

2,6-Me2-C6H3), but the bulkier pivalate (R = tBu) reduced reactivity, compared to acetate

(R = Me). The influence of the Ar group was explained as follows. The oligomeric species [ArPd(µ-O2CR)(PPh3)]n is in equilibrium with monomeric [ArPd(κ2

-O2CR)(PPh3)], as confirmed by IR spectroscopy, and the reactive form is only the

monomer. For Ar = Ph, the preferred form is a dimer (34), i.e. n = 2 (Figure 3). Bulky Ar groups favour the monomeric form over the inactive oligomer or dimer.96_This

situation is similar to what described by Hartwig for the reaction of cyclometalated complexes (Scheme 64).94_{Strangely, the reaction was found to be first order in both the}

dimeric species [PhPd(µ-O2CMe)(PPh3)]2 and the thiophene substrate,96 while in a

regime of pre-equilibrium between the monomeric and dimeric form half-order is expected.

Figure 3

Ozawa and coworkers went on with their studies on [ArPd(µ-O2CR)(PPh3)]n

complexes and evaluated their reactivity towards several different (hetero)arens. Reactivity ratios of several aromatic compounds towards [PhPd(µ-O2CMe)(PPh3)]2 are

shown in Figure 4. Particularly, benzothiazole reacted with [(2,6-Me2-C6H3

)Pd(µ-O2CMe)(PPh3)]4 in 1,4-dioxane at 65 °C to give a quantitative yield of the 2-arylated

product (Scheme 69). i_Pr

2EtN was added in order to suppress side reactions promoted

by the AcOH coproduct.97

Figure 4 – Reactivity ratios for several different heteroarenes towards [PhPd(µ-O2CMe)(PPh3)]2 in dioxane.96_{In bold the C-H bond which undergoes functionalization.}

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Scheme 69

It is worth-noting that benzothiazole is less reactive tha 2-methylthiophene, even though the latter is much more acidic (pKa = 27) than the former (pKa = 42).

Moreover, while the reaction was found to be first order in the concentration of 2-methylthiophene, it exhibited saturation kinetics with respect to benzothiazole. This fact was explained by the existence of a stable intermediate featuring coordinated benzothiazole: [ArPd(µ-O2CMe)(PPh3)(benzothiazole)] (35). This complex, indeed, was

produced in good yield by adding benzothiazole to a solution of the parent tetrameric complex in THF (Scheme 70) and has been characterized by NMR spectroscopy and X-ray diffraction.96 Pd O PPh₃ Ar O Me 4 1/2 Pd N PPh3 Ar O S O THF (77%) Ar = 2,6-Me2C6H3 35 Scheme 70

Deuterium KIE was also evaluated for both the substrates by determination of the kinetic constants by competition experiments, using 2-ethylthiophene as a common reference compound. 5-Deuterio-2-methylthiophene exhibited no measurable KIE, irrespective of the choice of starting complex and of the reaction conditions. On the other hand, 2-deuteriobenzothiazole provided kH/kD in the range from 3.3 to 5.5, thus

indicating that C-H bond cleavage is the rate-limiting step only for this substrate. The existence of a pre-coordinated, stabilized intermediated for benzothiazole enhances the activation barrier for the subsequent C-H bond cleavage process and explains the modest reactivity of benzothiazole compared to 2-methylthiophene. DFT calculations for the arylation of the latter heteroarene via the CMD pathway predicted that the rate-determining step would be C-C bond forming reductive elimination.97

Very recently Ozawa and coworkers98_{also performed kinetic studies on the effect}

of several different p-substituted derivatives of PPh3 (PAr3) on the reactivity of the

isolated complexes [(2,6-Me2-C6H3)Pd(µ-O2CMe)(PAr3)]4 (Ar = Ph, 4-MeO-C6H4,

4-F-C6H4, 4-CF3-C6H4). The latter complexes react with 2-methylthiophene and

benzothiazole to give good yields of the corresponding arylation products, as already shown for their analogues featuring PPh3 as a ligand (Scheme 68, Scheme 69).

The reactivity order is reversed according to the heteroarene substrate. The reaction with 2-methylthiophene is accelerated by electron-deficient PAr3, whereas that

with benzothiazole is enhanced by electron-rich PAr3. The reasons for these trends have

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rate-determining step for the arylation of 2-methylthiophene is reductive elimination97

and it is facilitated by electron-deficient PAr3. It is well known, indeed, that

electron-poor ligands assist this kind of process.99_{On the other hand, the rate-determining step}

for the arylation of benzothiazole has been shown to be the C-H bond cleavage,97_but

DFT calculations suggested that this step is relatively insensitive to the electronic properties of PAr3. In this case however, electron rich PAr3 destabilize the intermediate

[Ar’Pd(µ-O2CMe)(PAr3)(benzothiazole)] complex, thereby lowering the activation barrier

for the rate-limiting reductive elimination.98

Deuterium KIE was determined for the arylation of benzothiazole with all the aforementioned [Ar’Pd(µ-O2CMe)(PAr3)]4 complexes. Interestingly, while for Ar = Ph,

Ph, 4-MeO-C6H4, 4-F-C6H4 resulted that kH/kD is in the range 4.2-4.4, for Ar = 4-CF3

-C6H4 resulted kH/kD = 2.8. The authors have not commented this result.98

2.3 Cleavage of the C-H bond by carbopalladation /

dehydropalladation (Heck-type process)

In 2010 Itami and coworkers100_{reported that a variety of substituted tiophenes undergo}

regioselective arylation at the β positions by the reaction with aryl iodides in the presence of a PdCl2/P(OCH(CF3)2)2 catalytic system and Ag2CO3 as the base (Scheme

71). This result is peculiar, since the transition-metal catalyzed arylation of thiophene C-H bonds generally proceeds at α positions (C2 and/or C5) according to the typical reactivity profile of the thiophene ring in a CMD process.100_{The extremely}

electron-withdrawing ligand P(OCH(CF3)2)2 was found to be necessary for the regioselectivity of

the reaction and when it was substituted with ordinary phosphine (e.g. PPh3, PCy3) or

phosphite (e.g. P(OPh)3, P(OMe)3) ligands a reverse selectivity was observed.

Competition studies showed that electron-rich 2-methylthiophene reacts preferentially over electron-poor 2-chlorothiophene.100_{Fagnou and coworkers}49_{, however, demonstrated}

that with their Pd(OAc)2/PCy3HBF4/PivOH/K2CO3 method not only arylation at the α

position is favored but also acidic 2-chlorothiophene reacts preferentially over nucleophilic 2-methylthiophene (Scheme 72).

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Scheme 72

Itami and coworkers100_{tried to explain their results through an Heck-type}

reaction mechanism. PdCl2 undergoes reduction to a palladium(0) species in the reaction

environment101,102_{, which in turn reacts with the aryl halide to give a palladium(II)}

organometallic compound. The electrophilicity of this species is increased by the silver salt added in stoichiometric amounts, since the latter effectively sequestrates halide ions by the formation of highly insoluble silver halides. The tiophene substrate then gives Heck-type insertion into the Ar-Pd bond.100_{β-Hydride abstraction followed by reductive}

elimination of HX as well as concerted deprotonation – reductive demetallation would give the product and regenerate the catalyst.

The conventional Heck mechanism encounters a problem with the reaction of interest here, because the cyclic structure of thiophene limits the bond rotation after double-bond insertion. Specifically, there is no syn-hydride for the subsequent syn-β-hydride elimination step that is required in the traditional Heck mechanism101_.

Nonetheless Fu and coworkers, on the basis of DFT calculations, suggested that the reaction can also proceed through an anti-β-hydride elimination process.103_{Even though}

not common, anti-β-hydride elimination has been observed in several other cases104,105_,

including intramolecular Mizoroki–Heck reactions with α,β-unsaturated carbonyl systems which result in the product of a formal 1,4-addition and some intramolecular Mizoroki–Heck reactions with styrene-type alkenes101_{. The hypothesized Heck-type}

reaction mechanism for thiophene arylation is depicted in Scheme 73 together with the standard Mizoroki-Heck mechanism involving alkenes.

DFT computations also showed that the ligand P(OCH(CF3)2)3 may produce a

C-H-O hydrogen bond with hydrogen carbonate ion in the transition state, which is crucial for stabilization of the Heck-type transition state itself and, in turn, for the observed β regioselectivity (Figure 5).103

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Scheme 73

Figure 5

Itami and coworkers studied the reaction of [PhPd(bipy)(OAc)] (36) with 2-ethylthiophene,106_{which mimics the reaction conditions for the C4-selective catalytic}

oxidative coupling of 2-substituted thiophene derivatives with boronic acids catalyzed by a Pd(OAc)2/bipy system using TEMPO as the oxidant (Scheme 74).107 Surprisingly, they

found that in the absence of any additives the major product was the regioisomer arising from arylation at C5 (Scheme 75), while the catalytic process delivers the C4-arylated product with high regioselectivity. TEMPO was known not to influence regioselectivity.107_{The same experiment was repeated with the addition of 2-CF}

3-C6H4

-B(OH)2, this boronic acid has been chosen because it does not undergo transmetalation

under these reaction conditions. With this additive, regioselectivity was effectively reversed to the C4 position (Scheme 75). The authors postulated that the reason for this

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behavior is the formation of a borate complex [ArB(OH)2(OAc)]-, which is less basic

than free acetate.106

Pd(OAc)₂5 mol% bipy 10 mol% TEMPO 4 equiv PhCF3, 80 °C, 12 h (51-97 %) S R + ArB(OH)₂ S R Ar > 93% C4 selectivity Scheme 74 Scheme 75

The effect of a series of counteranions (PF6-, TfO-, CO32-, AcO-) introduced by

treatment of [PhPd(bipy)I] with the appropriate silver salts was evaluated. The formation of the C4 regioisomer was largely prevalent with the less basic anions (PF6-,

TfO-_{), while reverse selectivity was observed for CO}

32- and AcO-. Lewis-acidic additives

(Cu(BF4)2, Sc(OTf)3, BF3·Et2O) had the same effect as AgPF6 and AgOTf. In the

absence of any additive there was no reaction. The reactivity of 2-chlorothiophene with the aforementioned complexes was also evaluated. This electron-poorer substrate reacted with more difficulty than 2-ethylthiophene and yields were lower, but the same strong effect of counteranions on regioselectitvity was again found. These results pointed out that the catalytically competent species could be the cationic [PhPd(bipy)]+_.106

Computational studies were carried out on the cationic complex [PhPd(bipy)]+_.

An electrophilic aromatic substitution pathway was ruled out, in favor of a carbopalladation / dehydropalladation pathway, which was also in agreement with the observed regioselectivity. Unfortunately, due to the complexity of the system, the authors were not able to adequately analyze the deprotonation step using computational chemistry.106

Although at present there is no experimental evidence that supports a Heck-type reaction mechanism also for the direct arylation of other heterocycles, there are also no elements to rule it out definitively, and it is especially promising in the case of the use of silver salts as additives, since they lead to cationic palladium intermediates. This pathway, indeed, has been suggested by early workers for the arylation of several other heterocycles, especially furans and benzofurans45,108,109_{. However, evidence against an}

Heck-type mechanism for the vinylation of a benzofuran derivative has also been provided en route to the total synthesis of (-)-Frondosin B by the group of Trauner.110,111

The cyclization of optically active 37 gave intermediate 38 without significant racemization under the influence of a Pd(PPh3)4 and iPrNEt2 (Scheme 76). The authors

(43)

43

speculate that if a Heck-type process was operative, partial loss of optical activity would be expected in the case of syn dehydropalladation (Scheme 77).110

Scheme 76

Scheme 77

2.4 Cleavage of the C-H bond by other pathways

In 2007 Zhuravlev and coworkers112_{investigated some mechanistic aspects of the}

palladium-catalyzed direct arylation of benzoxazoles at C2. A Hammett plot was made for the direct arylation of several 5-substituted benzoxazoles 39 (Scheme 78). An excellent correlation was found for σ-, a poorer correlation for σp and no correlation with

σ+, σ·and σm constants113. Electron-withdrawing groups significantly accelerated the

reaction and a positive slope was found (ρ = 2.8). No significant deuterium KIE was found.112